This is the second blog post in the series of posts focused on the G6PD gene and G6PD deficiency. In this blog post, I provide an overview of the G6PD gene mutations with a particular focus on ones associated with G6PD deficiency. For other blog posts on the G6PD gene, please check the following list with corresponding links:
What Diseases are associated with The G6PD Gene Mutations?
Mutations in the G6PD gene have been associated with the following diseases:
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
Hemolytic anemia due to G6PD deficiency
Neonatal jaundice
How do the G6PD mutations affect the enzymatic activity of G6PD?
Different G6PD mutations cause quantitative and qualitative changes in the G6PD enzyme, but never with complete loss of activity, as complete loss of activity would be lethal [citation].
The consequence of G6PD mutations can damage hemoglobin so that red blood cells can be caught by macrophages or may succumb to hemolysis. [citation]. We explained the enzymatic activity of G6PD in the first post you can check it here. The conversion of nicotinamide adenine dinucleotide phosphate (NADPH) to its reduced form in erythrocytes is the basis of diagnostic testing for the deficiency. This usually is done by fluorescent spot test [citation], but we talk more about testing for G6PD deficiency in the fourth blog post you can check here.
How many G6PD mutations are there? What are the G6PD variants that affect the function of the G6PD enzyme? What mutation causes G6PD deficiency?
More than 400 mutation variants have been discovered in the G6PD gene [citation]. Most of these mutations are missense mutations that result from deletion, causing amino acid replacements that entail deficiency of G6PD enzyme activity because they compromise the stability of the protein or because the catalytic activity is decreased or through a combination of both mechanisms [citation].
What is missense mutation? A missense mutation is one of the three types of point mutations the other two types are a nonsense mutation and a silent mutation. Missense mutation corresponds to a change in a genetic sequence that leads to a substitution of one amino acid for another in a given protein being encoded by the gene in which the mutation is located. The nonsense mutation leads to the early termination of protein synthesis. The silent mutation leads to no detectable change in the protein encoded by the gene in which the mutation is located.
Based on G6PD enzyme activity and clinical manifestation, G6PD variants can be classified into the five classes in Table 1.
Table 1: Summary of G6PD variant classes
Class | Level of deficiency | Enzyme activity | Prevalence |
Class I | Severe | Chronic nonspherocytic hemolytic anemia in the presence of normal erythrocyte function | Uncommon; occurs across populations |
Class II | Severe | Less than 10% of normal activity | Varies; more common in Asian and Mediterranean populations |
Class III | Moderate | 10% to 60% of normal activity | 10 percent of black males in the United States |
Class IV | Mild to none | 60% to 150%of normal activity | Rare |
Class V | None | Greater than 150% of normal activity | Rare |
Over 60 mutations are described as Class I mutations, which comprise the most severe form of G6PD deficiency and lead to chronic non-spherocytic hemolytic anemia (CNSHA) [citation].
G6PD Mediterranean and the G6PD A– variants occur with increased frequency in certain populations [citation]. In North Africa, the Mediterranean variant is related to the C563T point mutation or also known as the Mediterranean variant (B-) [citation].
There are also reported combinations of mutations that result in G6PD deficiency. The variant G6PD A results from the point mutation A376G, whereas the deficient variant G6PD A- is characterized by the combination of the A376G mutation and one of the following mutations: G202A, A542T, G680T, or T968C [citation].
Furthermore, the deficient variant G6PD A-, in which a mutation in codon 126 (N126D, not causing G6PD deficiency), co-exists with one of three other mutations (M68V, R227L, L323P): it is the combination of the two mutations that cause G6PD deficiency [citation].
The only nonsense mutation has been found in a heterozygous woman [citation].
Currently, there are 230 G6PD gene variants with known mutations. Many polymorphic variants with high frequencies are related to some populations based on geographical location (Africa, Southeast Asia, the Mediterranean, and the Middle East).
G6PD deficiency is found on every continent [citation], and for example, variant G6PD A confined to the African population, and the Mediterranean G6PD variant is frequent in Caucasoids and Asiatics [citation].
How many G6PD mutations are point mutations?
Almost all G6PD deficiencies arise from different types of point mutations. As mentioned above point mutation may result in amino acid substitution [citation].
Is G6PD inherited from the mother or father, and if yes, how it works?
The G6PD gene is located on the sex-linked X chromosome. X-linked disorders affect males and females differently.
The X chromosome can be inherited from both the father and the mother. Because men inherit an X chromosome from their mother, if that particular chromosome carries the G6PD mutation, there is a risk of G6PD deficiency. Women inherit two X chromosomes, they have two copies of the G6PD gene, and both are rarely mutated.
In females, the mutated gene may be “masked” by the normal gene on the other X chromosome (due to random X inactivation)[citation].
What is random X chromosome inactivation? Random X chromosome inactivation occurs early in embryonic development in females and as the name explains it occurs randomly for one of the two X chromosomes. One of the two X chromosomes is permanently inactivated in cells other than germline cells (egg cells). Random X chromosome inactivation ensures that females, like males, have one functional copy of the X chromosome in each body cell. The other term for random X chromosome inactivation is lyonization.
In case one G6PD is mutated, symptoms usually do not occur. However, the events that trigger the onset of symptoms are certain foods, medications, or stress, followed by infection, which may demonstrate a mild onset of deficiency [citation]. Daughters of female carriers of an X-linked disorder have a 50% chance of being carriers themselves, whereas boys have a 50% chance of being affected.